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Further research demonstrates POTS cause


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I searched medline for this, and apparently not published yet. These guys (gals?) seem to have done most of their research on metabolic syndrome and panic disorder. It's nice to see them stretching their expertise over to POTS.

Back when I used to work in clinical research in the pharmaceutical industry, some of the best doctor/researchers that we worked with were in Australia. I don't know what it was, but they seemed to have bright inquisitive minds combined with really down to earth personalities. I think that intellectual curiosity is one of the most critical traits in medicine, yet unfortunately, sadly lacking in so many physicians. You are blessed to have this class of medical care.

In my experience, I would agree with lthomas521 in an earlier post on the other thread who said that 14 out of 14 was compelling. While you need large numbers when you're comparing one treatment vs another, but in looking at disease progression, small patient numbers can be very powerful. Of course, nothing is 100% based on 14 patients (statistically, nothing is 100% based on 1000 patients - it's all just about the "p" values), but I find what you've presented about this study to be very powerful.

Looking forward to seeing this article in print soon. We're taking our son to Mayo Jan 16th, so are optimistically hopeful that Dr. Low might be able to have some insights based on this research.

thanks so much for sharing this with us,


Edited by momdi
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For those who want to explore:

the gene is SLC6A2 and there is an article explaining the NET gene at: http://www.clinicalwindow.net/cw_issue_20_article3.htm

The article talks about NET (neuroephinephrine transporter) makeup. Toss aside the part about the role in heart failure and the article has a comprehensive description about the structure of the gene.

Also, information about the genetic map can be found at:


and there is a bunch of interesting stuff to click on there to see the alleles and everything.

I've only found 1 research study that contends that a mutation of SLC6A2 does not exist in POTS patients, but it was a really unreliable source and the study did not have a reliable proband.

My questions are centered around environmental exposures that may cause the mutation. That is to say, mutations that exist due to exposures in former generations or have occured to each patient in present time.

If anyone finds useful links on that- please post!

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I would be interested to know if they ever find a corrleation between methylation of the gene promoter - (turning the gene off) and autoimmune diseases, which so many of us seem to have in addition to dysautonomia. I wonder how all of this fits together? Very interesting.

Keep us posted.


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Guest Finrussak


I am a bit confused...I thought Linda moderated the NDRF site and here we have the very capable : Michelle and Nina and Melissa.

That aside, Id still be very interested in total numbers of participants and specifically their EXCLUSIONS. This is as important as numbers. i.e. I absolutely know that studies often exclude patients for many reasons, and these reasons can IN MY OPINION hide an agenda or bias. How do I "know"??? I have been personally involved as a scientist in such studies ( objecting strenuously until I left a few); my sister handles grants and studies for J and J; and my colleagues still do research; and finally both my older 2 are now involved in medical research and scientific studies. Can you find out the criteria for being accepted and/or excluded from this study???? and from what geographical area they are from??? Genetics is tricky within populations that are closely related...the results can more easily be inferred to "everyone" when a larger variation is used ( different races, sexes, ages, med histories, geography etc).

Im not anti- any study, Im just very wary of terms like "all" and "every" like the conclusion that they have "denervation was not found in any with POTS"...well, I have POTS along with other stuff and I have neuropathy, and less nervous impulses ( denervation) in various areas of my body...and it is a guess if the latter is a causative or comorbidant factor==chicken or egg, and useless at this point...it IS what it IS so we handle the now. The first thing I teach an undergrad science class is to never write a report or study conclusion using the following " all, never, everyone, etc"...when it doesnt specifically mean the actual participants and when results are being inferred.

As for the Norepi uptake it is fascinating and may indeed prove useful to a majority of "us" HOWEVER I still am skeptical of it being "the answer" to EVERY POTSy...again using myself as an example...we have experimented on various agents that both increase Norepi uptake and block it and apparently I have NO problems with Norepi...More doesnt alleviate sx ( assumably then I am not having shortages) and less/blocking slightly worsens things ( assumably then I dont have too much). Yes, I may be a big exception but as I read other posts it's apparent how many are "different".

Id also be interested in seeing the reuptake within the brain...many of us have brain chemical issues that may be instead of or even addition to heart norepi uptake patterns. Perhaps the problem with norepi starts in the brain, and eventually affects the heart??? and maybe the remethylation is in response TO whats going on and not necessarily the "cause"???

Plus remembering back to teaching histology and physiology...Im thinking that heart tissue is hard to use for generalizations...higher mitochondrial requirements and activity etc...the research is GOOD to add to current data but again I find it hard to accept the broadbased generalizations made.

For those it may help, I wish them well...and its truly exciting...BUT as this forum has so many with variable causes and even diff dysautonomias ( i.e. a few here may not have POTs but OI) to starkly a definitive research is very disheartening.

as for MIBG...this scan can be very dangerous for those like myself having severe iodine allergies!!! even with pre-meds I have had problems. I hope they come up with other safer tests.

as for the gene in question's role in heart failure what is VERY interesting is that there seem to be a few studies lately about CFS sx that are amazingly similar to dysauto that are being compared to heart failure!!! or more accurately that the CFS may be a protective response of some person's bodies to prevent severe heart failure...this study was cited on another post by Sophia...anyone interested can ask her for it.

any further details or even the study itself will be most helpful. Thanks for keeping us apprised of all developments!!!

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Guest Julia59

I just wanted to another research abstract that I had sent to Michelle a couple weeks ago.


nitric oxide


A colorless, poisonous gas, NO, produced as an intermediate during the manufacture of nitric acid from ammonia or atmospheric nitrogen and as a product of cellular metabolism. In the body, nitric oxide is involved in oxygen transport to the tissues, the transmission of nerve impulses, and other physiological activities.

Julie :0)

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Guest Finrussak

Thanks Julie...only was able to briefly scan the abstract...but if Im correctly processing it, seems like the genetics around the NO can then affect the norepinephrine variables. So its complex as we tease out the genetics along with the chemical pathways, many genes may be in play and therefore many causes and effects and treatments.

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Finrussak, the interventions you described in your case don't provide any evidence against the norepinephrine transporter deficiency theory, not even in your own case. If someone doesn't have norepinephrine transporters to begin with, then taking something that would alter the activity of the norepinephrine transporters (if they existed) should have no effect, at least as far as norepinephrine reuptake is concerned. If they don't exist, you can't increase or decrease their activity. That would be like turning the "dimmer switch" up or down on a light fixture with no bulb in it. So the fact that these agents didn't help you hardly disproves the theory that the norepinephrine transporter gene has been switched off.

Of course, there's nothing that says that you can't have other neurological problems besides POTS. If you have denervation, you have denervation. Have you had a tilt-table test? If you had a negative result on the tilt-table, you wouldn't have been eligible for inclusion in the study. So maybe you have a completely different disease to begin with.

Fortunately, there would be no point in doing an MIBG in your case. If you want to measure how bad someone's NE reuptake is, you just take a blood sample when they've been lying down for a while and another after they've been standing. They routinely do that for POTS patients in some centers.

We haven't read the actual study yet, but it wouldn't bother me to see the researchers say that "all" of their case subjects had hypermethylation of the NET promoter region or that "none" of them had denervation in the legs. If that's what they found, then that's what they found. I am particularly encouraged by the possibility that they included anyone with a positive tilt-table test. If you find a bizarre finding in a motley collection of people who have really only one thing in common, I think that's compelling. If every single one of these people didn't have denervation, I think that's also compelling, because it contradicts a common theory.

Nevertheless, I agree that it is important to consider the inclusion and exclusion criteria of a study carefully, because they can be used to bring about misleading results. For example, some people in the CFS community argued that the studies that purported to show that "cognitive therapy" and "graded exercise" were beneficial for CFS patients didn't use a proper case definition for CFS. The studies allegedly used the Oxford criteria instead of the CDC case definition, and therefore included a lot of people who wouldn't have fit the more stringent CDC case definition. So, people who didn't really have CFS but benefited from graded exercise and cognitive therapy would muddy the findings. Some people have argued that this was a deliberate ploy on the part of British psychologists to get CFS defined as a psychological disorder rather than a medical illness, thus increasing trade for the psychologists. You can read more about the controversy at http://www.masmith.inspired.net.au/docs/pacing.htm.

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I am amazed. totally amazed. I have been living with POTS for at least 25 years. When I was first struggling with POTS, doctors told me I was neurotic and I needed a psyciatrist and if I would just calm down everything would be fine.

Then in the 90s came more understanding and a few doctors that were specializing in treating POTS patients.

Now, it seems to me there has been an explosion in studies and great strides in understanding the mechanism(s) of POTS. I find myself daring to hope that it may not be too late for me (I'm 58) to get better. Surely, the more POTS is undertood the better treatments will become.

Julie, thank you for posting the link to the article you found. I can't imagine how the information on NO and the new information on the gene promotor in Dr. Esler's study are related. If there is anyone here who can read and understand the article Julie found and the study results of Dr. Esler's and offer thoughts on how these things might go together, I would like to read and ponder your thoughts.

Again, I am truly amazed. I had come to an acceptance of having POTS and that I will never get better. I actually have hope. That is truly amazing. AMAZING!

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Guest Finrussak


thanks (really) for inspiring me to review..as per Cardiovascular Sytem Review text by Rogers and Hamburg:

{NE is released from a varicosity and binds to postjunctional receptors. These

adrenoreceptors fall into two major classes: alpha (a) and beta (:). These receptors

are further subdivided into a1, a2, b1, b2, and b3 designations. NE is inactivated

through reuptake by neighboring cells or the original nerve varicosity. Once inside,

NE is put back inside vesicles by a special transporter protein. By inhibiting these

reuptake proteins, it is possible to upregulate sympathetic activity to these organs. In

addition, tyramine, an amino acid, is taken up with such affinity by nerve varicosities

that it actually displaces NE from the vesicles. The resulting flood of NE effectively

causes sympathetic nerve upregulation.}

Im assuming the "special transporter protein" which effects the reuptake is what we are discussing?? The methylation of the gene would then stop protein production, right? well, then again Im assuming here but if I or anyone with a lack of transporter OR a total/near total shut down of the gene ( deletion etc) then we would have to have abnormally high levels of norepinephrine??? and a mostly steady state of "sympathetic upregulation"?

Its possible that I am misinterpreting this as biochem was NOT my strong suit, then or now....but

The few ( and I admit its very few) studies Ive been able to plow thru tonite indeed show the chemistries of such pts to have non-normal levels of norepi due to lack of reuptake INTO the cells. There are also pts with high norepi presumably due to overproduction ( unk if its genetic or other reasons) without comparable reuptake. apparently the body can re-absorb just so much into the cells. Others simply seem to stop producing as much NE, as none or little is being put back into storage thereby affecting the feedback cycle

I dont think therefore that in my case I could possibly have transporter deficiency as my levels arent abnormal unless in episode--and I suppose the drugs I tried may be affecting something but its not affecting NE uptake or being overridden??

Im finding it difficult to use your bulb metaphor, but wouldnt the electricity be the norepi?? and the dimmer the reuptake transporter proteins in that they regulate how much norepi/electric gets thru amd how much is put back into vessicles. The bulb would be the cells being finally affected? In this way Norepi/electric is being produced and if no dimmer( reuptake), it flows unheeded into bulb , upregulating the system ( bright bulb)...too much dimmer ( larger numbers of transporter proteins produced), too much reuptake norepi and then a dim bulb?

AND what if some of us have a TYRAMINE problem??? too much or too little??? anyone with knowledge of tyramine studies??? Id like to know and am too exhausted to go further for now!!!

Confusing but thanks for the exercise,,,I needed the cognitive workout. Id love to continue these high powered discussions with you...quite enjoyable and sorely missed I assure you.

somehow tho I fear we both may be missing the point

in answer to your queries:

I have had POSITIVE as well as equivocal tilts...and have been definitively dx by Dr Grubb with absolutely POTS and OI due to several factors Ive already posted elsewhere. and as Ive said, when between episodes my NE and other values work fine with position changes until the adrenaline rises to a threshhold level ..so Dr Grubb is guessing that my POTs et al may not be within the norepi reuptake category! Of course it may still be an over/underproduction situation or overly sensitive cell receptors that bind with NE. Cell surface receptors are not the same as reuptake receptors. The former binds NE and effect a change( a release of something or change in conductivity), while the latter causes the NE to be " put back inside" sort of storage.(effectively removing it from circulation)

as far as my comment of using "all" /"none"...I wasnt refering to using them to refer to subjects within a study. I was objecting to using those words in reference to broader generalizations/extrapolations and applications to others not in the study. Reporting results must be accurate, so that if EVERY subject had a response, of course it should be reported as such. It is in the "conclusions" section in which relevance is addressed -thats the problem. Attributing a characteristic of one small population to all afflicted.


I was quite serious ,tho didnt want to sound merely "contentious"...honestly!

I myself have been excluded from studies of a very well known POTS researcher, who I believe really wants to help people, in a prominent med center that many here go to regularly...and my own Drs have been told it was due to not wanting to "mess up and further cloud" the expected and hoped for results!!!!! The very same researcher has declined to see or examine me for tx based upon my not "fitting his needs at the moment for research subjects" as well! as if trying to help me was a waste of his time...I was sitting in a consult room and he was on speaker phone with my cardio!!!! ethical...maybe...maybe not- but nonetheless I will attest to this as TRUE!!!

again - that Dr has produced volumes of very helpful info for many...He deserves every bit of the respect and appreciation...that doesnt change the fact of what can and often does "bias" studies!


Whenever you are up to an encapsulation of the study...and possibly cross correlation with the NO stuff.

Anyone else, including Lthomas...anything on the tyramine wrinkle?? Im thinking a possible tyramine glitch where there is too little and not enough to displace the NE, causing nore uptake and therefore a decrease in circulating NE OR conversely too much tyramine, displacing a lot of NE and causing it to be higher in circulation??

interesting and amazing stuff, indeed!


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Important when discussing the correlation with Heart Failure. HF is an incidence of insufficient NET activity- not the other way around. To make the picture complete, an increase load of Seratonin activity would have to be present and you would have another problem that would cause that. It may be possible to mimic the recipe if you were older and loaded up on caffeine and stims every day- but just keep it in mind. We don't want people to panic here!

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Guest Finrussak


THANK you!!!! I have fwd the article to myslef and will read carefully once the Lyme fog lifts...but at first glance it seems that they didnt include anyone in stufy who has orthostatic hypotension...

I fiond it interesting that even they accede the point of the many variances in dysauto and even OI, and wanted to isolate one population to study ( a good thing) but admit then that after they cant generalize about others with overlapping sx.

I also find funny theyre basic conclusion that we are " messed up" or in their words have " disordered responses"...no kidding LOL


I am sure I wasnt trying to link heart failure with dysauto sx...just that with all the confusing overlaps its interesting to me that CFS is being compared to HF or specifically as a preventative to "real" HF, and with many chemical and sx similarities of CFS to the varying dysauto's, and how many of the researchers in all 3 areas are looking at NET and irregularities, it becomes a topic of conversation as to how if at all , the info is related...a commonality we shouldnt overlook.

Plus many of us ( I def do) have irregular seratonin levels...whether baseline or just while episodal...these chemicals are very intertwined.

Like back a few years when researchers noticed the connection between neuropathy and glucose levels...the commonalities started to make sense and they ( neuros and endos) started to cross connect data. Got to a theory of which causes what. But by no means is the picture absolutely black and white clear. there are many diabetics w/o neuropathy and many non-diabetics WITH....its just that on average a higher blood glucose will make it more liekly than not that youre at higher risk to develop neuropathy.

organisms dont function in a vacuum...everything affects ( good or bad) all else...sometimes simply domino effect, other times cascade effect etc etc...

and btw do you know if the state of research in HF is at the point where they can absolutely tell if the NET snafu comes before or after??? Im guessing not many HF pts have had the need for prior studies to see if their NET was having probs before the HF, or if their genetics predisposed them to it...

curiouser and curiouser ( said Alice) POTShole/ rabbit hole...all the same to me

thanks again, all

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Wow, great information! I enjoy reading your posts and I feel like I'm getting a top education just reading through all the links for information you have so graciously provided. Although, I must admit it does take me longer than most to understand things because I have to look up the meaning of some of the terms but hey, I'm lovin' it....Thank you for taking the time to put it out there for us to learn from.

I would be curious to know what information you may be willing to share on chronic pain. I've been trying to research information regarding EDS and why exactly it seems to cause chronic pain within the bone itself. etc....and the bodys reaction to chronic long term pain, etc.

Again, thank you for your time and best wishes.

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'Im assuming the "special transporter protein" which effects the reuptake is what we are discussing?? The methylation of the gene would then stop protein production, right? well, then again Im assuming here but if I or anyone with a lack of transporter OR a total/near total shut down of the gene ( deletion etc) then we would have to have abnormally high levels of norepinephrine??? and a mostly steady state of "sympathetic upregulation"?'

Actually no - all POTS patients that the guys at the institute were testing reported similar symptoms to some degree (presyncope, tachycardia, orthostatic intolerance) as well as our own unique symptoms - but all also waxed and waned in symptoms. This theory certainly doesnt explain why this is the case. It might even suggest an autoimmune issue - perhaps an antibody hampering the regulation of an enzyme that results in over-methylating the promoter? Im not sure.

Ive been emailing the Professor to discuss these possibilities but he is away on xmas leave.

Im looking forward to Linda's feedback.

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I'm glad you brought up the "waxing and waning" of symptoms. Also, symptoms sometimes change and different ones become problematic. I also was wondering how a methylation of a gene promoter can cause such changing? I picture a "turning off" of a gene promoter as a "constant". I don't picture it as changing.

Maybe the fact that we have such "dysregulation" causes our bodies to constantly seek a "steady state" in reaction to a constantly changing environment both internal and external?

Ahh... More to research... more to figure out... but every little bit helps. It's all interesting nonetheless.

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Guest Julia59

Jan---I posted the abstract because I thought it was interesting. :o I'm still trying to translate it myself.

I'm with you----can anyone help us understand this abstract I posted.

"NO produced by endothelial NO synthase is a significant factor in the regulation of blood flow."

"According to 2-locus genotype analyses, patients with -786CC and 298EE or 298ED experienced the largest changes in heart rate and plasma norepinephrine with standing. These results indicate that NO may influence the development of POTS and the severity of POTS symptoms."

This was posted on Pub Med in Nov 2005---it's a recent article.

Here's the full abstract:

Endothelial NO synthase polymorphisms and postural tachycardia syndrome.

Garland EM, Winker R, Williams SM, Jiang L, Stanton K, Byrne DW, Biaggioni I, Cascorbi I, Phillips JA 3rd, Harris PA, Rudiger H, Robertson D.

Autonomic Dysfunction Center, Vanderbilt University, Nashville, TN 37232-2195, USA. emily.garland@vanderbilt.edu

Postural tachycardia syndrome (POTS) is a heterogeneous disorder characterized by an excessive rise in heart rate and symptoms consistent with cerebral hypoperfusion in the upright position. NO produced by endothelial NO synthase is a significant factor in the regulation of blood flow. Genetic polymorphisms in the promoter region (T-786C) and exon 7 (E298D) of the NO synthase isoform 3 gene affect enzyme activity and have been associated with a number of cardiovascular diseases. Because some findings in POTS suggest aberrant NO-mediated functions, we postulated that the variant genotypes of these polymorphisms may increase the risk of developing POTS and correlate with more severe symptoms. We genotyped 136 patients with POTS (mean age 32.2+/-9.9 years; 46 men and 90 women) from Nashville, Tenn, and Vienna, Austria, and compared them with 191 healthy volunteers (mean age 29.1+/-8.0 years; 127 men and 64 women). Participants also underwent orthostatic testing with blood pressure, heart rate, and plasma norepinephrine measurements while supine and upright. The frequencies of the -786CC and 298DD genotypes were significantly lower in patients with POTS than in control subjects (odds ratio [OR], 0.28; 95% confidence interval [CI], 0.14 to 0.57; P=0.001 for -786CC; and OR, 0.44; 95% CI, 0.21 to 0.91; P=0.033 for 298DD). According to 2-locus genotype analyses, patients with -786CC and 298EE or 298ED experienced the largest changes in heart rate and plasma norepinephrine with standing. These results indicate that NO may influence the development of POTS and the severity of POTS symptoms.

As you can see the study subjects are from the US and overseas.

Julie :0)

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